Dietary and Lifestyle-Centered Approach in Gout Care and Prevention

Abstract

Purpose of review

We aim to provide a comprehensive review of the available literature to inform dietary recommendations for patients with gout and hyperuricemia that have the potential to simultaneously lower serum urate and reduce gout morbidity while addressing gout’s cardiometabolic comorbidities holistically.

Recent findings

The global burden of gout is rising worldwide, particularly in developed nations as well as in women. Patients with gout are often recommended to follow a low-purine (i.e., low-protein) diet to avoid purine-loading. However, such an approach may lead to increased consumption of unhealthy carbohydrates and fats, which in turn contributes to metabolic syndrome and subsequently raises serum urate levels and leads to adverse cardiovascular outcomes. On the other hand, several well-established diets for cardiometabolic health, such as the Mediterranean and Dietary Approaches to Stop Hypertension (DASH) diets, in combination with weight loss for those who are overweight or obese, also have beneficial effects on relevant gout endpoints.

Summary

It is important to recognize not only the direct effect of diet on hyperuricemia and gout, but its mediated effect through obesity and insulin resistance. Thus, several preeminent healthy dietary patterns that have proven benefits in cardiometabolic health have the power to holistically address not only gout morbidity but also its associated comorbidities that lead to premature mortality among patients with gout.

Premise

The global burden of gout morbidity and comorbidities are on the rise and have trended closely with the obesity epidemic [1•, 2•, 3•, 4]. In a recent review [5], we outlined the existing evidence in support of healthy diets, such as the Mediterranean or Dietary Approaches to Stop Hypertension (DASH) diets, to address gout as well as its cardiometabolic comorbidities synergistically. Here, we present a more in-depth review of the literature on several different factors that have all converged to give rise to the modern gout epidemic, and how they can be traced back to the widespread adoption of Western lifestyle trends, particularly diet. We also present practical approaches to the integration of dietary guidance on comprehensive gout morbidity and comorbidity management.

Global Morbidity Burden of Gout on the Rise

Gout incidence and prevalence has steadily increased worldwide, resulting in excess healthcare utilization among patients with gout at high personal and societal expense. Two recent analyses of the Global Burden of Disease Study have revealed rising burden of gout worldwide between 1990 and 2017, especially in developed nations and among women [1•, 2•]. It is estimated that globally, more than 41 million individuals are afflicted with gout, with 7.4 million incident cases per year and 1.3 million years lived with disability according to 2017 estimates [1•]. A population-based study out of Olmsted County, Minnesota, revealed a more than doubling of the incidence rate of gout from 1989–1992 to 2009–2010, from 66.6 per 100,000 population to 136.7 per 100,000 population; similar results were observed across different age groups and sex [3•]. Furthermore, in an analysis that compared US hospitalization trends between patients with gout and rheumatoid arthritis (RA) from 1993 to 2011, primary hospitalization rates for gout increased substantially over the prior two decades, while those for RA declined, such that hospitalizations for gout surpassed that of RA by 2011 (8.8 vs. 4.6 hospitalizations per 100,000 US adults, respectively) [6]. Similar trends in gout hospitalizations have also been observed in Canada [7], England [8], and Sweden [9, 10].

Contemporary Burden of Gout Comorbidities

In our prior review, we highlighted the high prevalence of cardiometabolic comorbidities among patients with gout due to the shared pathogenesis of insulin resistance [5]. As the burden of gout has continued to climb in recent years, so too has the burden of its comorbidities. Contemporary analyses have revealed that the comorbidity profiles of patients with gout at time of diagnosis have worsened [3•, 4, 11]. For example, the aforementioned study out of Olmsted County, Minnesota, revealed that the prevalence of class II and III obesity (body mass index [BMI] ≥ 35 kg/m²) among gout patients nearly tripled from 10% in 1989–1992 to 29% in 2009–2010 [3•]. There was also notably higher prevalence of cardiometabolic comorbidities including hypertension, diabetes, and renal disease in the later cohort (Table 1) [3•]. Such comorbidities, including ischemic heart disease, hypertension, and obesity/elevated BMI, have been associated with recurrent gout flares and the odds of frequent flares (≥ 2 per year), in cross-sectional [12] and longitudinal studies [13–15]. They are also critical as they can directly contribute to premature mortality among patients with gout. For example, an analysis of the UK general population revealed that patients with gout experienced excess mortality compared to their non-gout comparison cohort between 1999 and 2006. Furthermore, this excess mortality observed among patients with gout persisted in the more recent 2007–2014 cohort, reflecting a lack of improvement in excess mortality among individuals with gout [16]. These results were particularly noteworthy when compared to the same analyses conducted among patients with RA, which showed a reduction in excess mortality among patients with RA in the later cohort, likely reflecting an improvement in RA management [17]. Thus, there is a substantial need to consider comorbidities of gout in addition to its morbidities in holistic gout care, where cardiometabolic diets can play a major role.

Table 1.

Rising prevalence of comorbid conditions at time of incident gout diagnosis in Olmsted County, Minnesota

Comorbidity	1989–1992 (n=158)	2009–2010 (n=271)	p-value
Body mass index, kg/m2, median	28.3	30.9	<0.01
Body mass index ≥30 kg/m2	37%	56%	<0.01
Hypertension	54%	69%	<0.01
Heart failure	6%	10%	0.20
Diabetes mellitus	6%	25%	<0.01
Renal disease	11%	28%	<0.01
Coronary artery disease	23%	20%	0.43
Stroke	4%	7%	0.24
Hyperlipidemia	21%	61%	<0.01

Adapted from: Elfishawi et al., J Rheumol 2018

Evolutionary Biology, Ecologic Data, and Gout Frequency Trends

Unlike other mammals, humans and the great apes both lack uricase, an enzyme that converts uric acid into the more soluble compound allantoin; however, humans are the only mammals known to develop gout spontaneously [18, 19]. The impact of diet on serum urate levels in these species that lack uricase provides insight into why serum urate levels in the great apes (1.5 to 3.0 mg/dL) [18] are substantially lower than those in humans in the modern era (e.g., mean serum urate 6.0 mg/dL among men in NHANES 2015–2016) [20]. The most notable difference in the dietary patterns of great apes and humans is that great apes primarily consume fruit and vegetation while their animal protein intake is minimal [18], in stark contrast to a typical Western diet today.

Early humans in indigenous scavenging and gathering societies who lived on traditional diets primarily derived from fruits and vegetables, with sporadic supplementation with game and fish, likely had serum urate levels similar to those of great apes [18]. However, with the increasing uptake of Western culture and dietary habits, including abundance of fatty meats and refined carbohydrates and relative paucity of dairy products, hyperuricemia and gout have become an epidemic, closely mirroring similar trends in obesity, including among some native peoples, such as the Maori of New Zealand [18, 21, 22]. Similarly, gout was rare among Blacks in Africa, especially in rural communities with traditional agricultural and dairy-based diets, but its prevalence has been increasing, especially in urban communities [18]. Among Blacks in the USA, gout was considered rare in the early 1900s, but changes in diet have led to a rapid development of obesity, diabetes, and hypertension such that today, the mean serum urate and prevalence of gout is higher among Blacks than among Whites in the USA [18, 23].

Furthermore, ecologic studies of Japanese [24] and Filipino [25] populations have found that US immigrants from these countries had elevated serum urate levels and adiposity, compared with those who continued to live in their original countries. Similarly, the Tokelau Island migrant study found that the incidence of gout between 1968 and 1982 was 9 times higher in the migrant men living in urban New Zealand than in the non-migrant men in Tokelau, paralleling increased adiposity and frequency of type 2 diabetes during the same period [26, 27]. Finally, epidemiologic studies from Canada, Europe, New Zealand, Hong Kong, and China all reported that gout incidence and prevalence have increased [21, 28–32] correlating with worsening obesity and metabolic syndrome trends [33–36].

Mendelian Randomization Analyses and Physiologic Evidence

While the casual relationship between hyperuricemia and metabolic syndrome has been debated for decades, recent Mendelian randomization studies suggest that serum urate itself is not causing obesity or related traits of the metabolic syndrome [37–41], nor type 2 diabetes itself [42–45]; rather, several traits of the syndrome are casual to serum urate and gout, including adiposity [37, 38, 46–48], insulin resistance, and certain lipid components [49]. In our recent bidirectional, one- and two-sample Mendelian randomization analysis [50], neither genetically predicted serum urate levels nor genetic liability to gout were causally associated with fasting insulin levels; conversely, genetically predicted fasting insulin levels conferred significant increases in serum urate (e.g., 0.63 mg/dL per SD of fasting insulin) and gout risk, even with adjustment for BMI.

These causal inferences are consistent with previous reports that found higher levels of insulin resistance reduced renal excretion of urate [51–54]. For example, exogenous insulin can reduce the renal excretion of urate in both healthy and hypertensive subjects [51, 52, 55]. Insulin could enhance renal urate reabsorption via stimulation of GLUT9 [56] or other renal urate transporters [57]. This paradigm would also be consistent with the observation that hyperuricemia in humans results from the underexcretion of uric acid in the vast majority of cases (90%) [19]. Another causal indicator included in the most recent serum urate genome-wide association study [58], the genetic causal proportion, provided further evidence that adiposity, fasting insulin, and triglycerides are partially genetically causal to serum urate. Indeed, serum urate and triglycerides have been shown to mediate the causal pathway between genetically predicted BMI/body fat and the endpoint of gout [47, 59].

Perfect Storm: Western Lifestyle Perpetuating Cascades of Risk Factors for Gout

In sum, the widespread adoption of Western lifestyle trends has created a confluence of several different factors all feeding into the modern gout epidemic (Fig. 1). In the last few decades, we have been eating more in terms of calories and portion sizes [60], eating worse in terms of refined carbohydrates (including high-fructose corn syrup) and trans or saturated fat, and exercising less, all contributing to the obesity epidemic [5, 33, 61, 62, 63••, 64], which has undoubtedly contributed to more individuals developing hyperuricemia and gout. The importance of this mediated effect through obesity is highlighted by studies which have found that increases in BMI [65] and total body weight [66] during adulthood were associated with increased serum urate levels and risk of incident gout, respectively, in general population–based analyses from South Korea [65] and the USA [66]. Similarly, recent analyses have revealed that 44% of hyperuricemia cases in the US general population [63••] and 31% of incident gout cases among male health professionals [67••] could theoretically be prevented by eliminating overweight/obesity. Furthermore, this obesity epidemic has resulted in increasing prevalence of the metabolic syndrome, as well as hypertension, end-stage renal disease, and congestive heart failure, all risk factors for hyperuricemia and gout [68–70]. Finally, the medications needed to treat these cardiometabolic conditions, such as diuretics, low-dose aspirin, and transplant immunosuppressive medications, are those known to increase serum urate and also contribute to gout risk [68–70].

Fig. 1.

Confluence of several different factors all feeding into the modern gout epidemic

Below, we outline the ways in which healthcare providers can assist their patients in making informed dietary decisions to integrate into their gout care plan. Although reversing the obesogenic environment in which we find ourselves in is no simple task, healthy lifestyle changes, even on a relatively smaller scale, hold the power and promise to slow down the worsening global burden of gout and improve gout morbidity and comorbidities.

Traditional Dietary Approach for Gout

Presently, the most common dietary advice given to patients with gout is to follow a low-purine diet, which essentially translates to a low-protein diet, in an effort to reduce purine-loading [71]. Although widely advocated and often treated as dogma, the long-term therapeutic value of such an approach is questionable at best, given its limited palatability, sustainability, and anti-gout efficacy [54, 71]. Indeed, individuals with gout have reported difficulties in reconciling aspects of the traditional “gout” diet (e.g., low protein, avoidance of purine-rich vegetables) which conflict with dietary recommendations for managing their concurrent type 2 diabetes (e.g., increasing protein intake) and cardiovascular risk [72]. Furthermore, when the intake of one macronutrient (e.g., protein) is reduced, this must be accompanied by an increase in intake of one or both of the remaining macronutrients (e.g., fats or carbohydrates) to maintain stable energy intake which is tightly regulated by homeostatic mechanisms. Although it is possible to replace protein with healthy carbohydrates and fats that would not necessarily lead to detrimental health effects, given the prevalence of Western-style diets and widespread adoption of unhealthy eating habits [73], there is the risk of protein-restriction leading to increased consumption of refined carbohydrates (including fructose, a well-recognized risk factor for hyperuricemia and gout) [74, 75] as well as saturated and trans fats. These dietary composition changes have the potential to exacerbate insulin resistance, leading to higher levels of plasma glucose and lipids, and thereby contributing to worsening of metabolic syndrome and its associated comorbidities in patients with gout [54, 71].

Diets for Cardiometabolic Health

There are multiple evidence-based healthy cardiometabolic diets that improve cardiometabolic health, including the Mediterranean and Dietary Approaches to Stop Hypertension (DASH) diets. These diets, have been endorsed by the American Heart Association (AHA)/American College of Cardiology (ACC) [76] as well as the Dietary Guidelines for Americans 2020–2025 [77], are widely recommended and implemented in routine clinical practice, and are much more sustainable in the long term than a conventional low-purine diet. Although there are some differences in the foodstuffs that are emphasized or deemphasized in each of these diets, importantly there are several overarching themes including emphasis on whole grains, healthy unsaturated oils, vegetables and fruits, nuts and legumes, and healthy protein such as poultry, fish, eggs, and low-fat dairy while limiting the consumption of red meat, refined carbohydrates, and saturated fats (Fig. 2) [5]. Numerous analyses have illustrated the benefits of substituting these foodstuffs for less healthy options on cardiometabolic outcomes relevant to gout, including reduced risk of coronary heart disease (CHD) [78, 79], obesity [80], type 2 diabetes [81], and metabolic syndrome [82, 83].

Fig. 2.

Comparison of mediterranean and DASH diets

*Fish & Seafood are exceptions where short-term recommendations (for gout flares) and long-term recommendations (for cardiometabolic health) may be contradictory. Long-term, patients with gout would still benefit from moderate fish & seafood consumption if their gout/hyperuricemia is sufficiently controlled by other measures.

The Mediterranean diet has been associated with improvements in cardiometabolic risk markers [84–88] such as lipid profiles and fasting blood glucose and has well-established benefits with regard to cardiometabolic outcomes. [84, 89–97] In randomized trials, this diet was associated with a >50% lower risk of incident type 2 diabetes [96] and 73% lower rate of coronary events and 70% lower rate of total mortality for secondary prevention of acute coronary syndrome (Table 2) [95]. Furthermore, in a 2-year randomized dietary weight loss trial, the Mediterranean diet led to greater sustained weight loss and better glycemic control than a lowfat diet [99]. Importantly, the 2-year adherence rate of the Mediterranean diet in that trial was 85% [99] and a recent 5-year randomized controlled trial also showed high adherence [89], suggesting that such a dietary strategy may be more sustainable than the conventional low-purine diet currently recommended for patients with gout.

Table 2.

Randomized trials and secondary analyses reporting on the effects of the Mediterranean diet on gout/hyperuricemia and cardiometabolic endpoints

Trial (N*)	Gout/hyperuricemia effects	Cardiometabolic effects	Comments
PREDIMED (n = 7447 with high risk of CVD)	73% ↑ odds of reversal of hyperuricemia* among those with baseline hyperuricemia among those with the highest quintile Mediterranean diet (Med diet) adherence as compared with the lowest [98]. 23% ↓ odds of prevalent hyperuricemia among those with highest quintile Med diet adherence as compared with the lowest [98].	28–31% ↓ risk of major CV event (myocardial infarction, stroke, and death from cardiovascular causes) compared with control diet [89]. 51–52% ↓ risk of incident T2DM compared with control diet [96].	Serum urate data derived from n = 4,449 participants with serum urate data available [98].
Lyon Diet Heart Trial [95] (n = 605 with history of myocardial infarction)	N/A	73% ↓ rate of coronary events, compared to a usual post-infarct “prudent” diet (i.e., secondary prevention). 70% ↓ rate of total mortality.
DIRECT [99] (n = 322 overweight/obese subjects)	0.8 mg/dL ↓ in serum urate at 6 months in Med diet group compared to baseline [100••]. Among those with baseline hyperuricemia (SU ≥ 7 mg/dL), 2.1 mg/dL ↓ in serum urate at 6 months in Med diet group compared to baseline [100••].	4.4 kg ↓ weight loss in Med diet group compared to baseline. 6.3 mg/dL ↑ in HDL and 21.8 mg/dL ↓ in triglycerides in Med diet group compared to baseline. 32.8 mg/dL ↓ in fasting glucose and 4.0 μU/mL ↓ in fasting plasma insulin in Med diet group compared to baseline.	Med diet with calorie restriction. Serum urate data derived from n = 232 participants with serum urate data available [100••].

Med diet Mediterranean diet

^*N represents that of original trial

In terms of urate-lowering benefits, a secondary analysis of the aforementioned 2-year randomized dietary weight loss trial [99] demonstrated that a Mediterranean diet combined with calorie restriction resulted in a mean serum urate reduction from baseline of 0.8 mg/dL in the study population as a whole; this reduction was even more pronounced among those with baseline hyperuricemia (defined as serum urate ≥7 mg/dL), with a mean reduction of 2.1 mg/dL [100••]. Similar results have also been reported in other analyses using the endpoint of hyperuricemia [98] as well as for incident gout [101].

The DASH diet, initially developed and studied for the prevention and reversal of hypertension, is well recognized for its ability to bring about significant reductions in both systolic and diastolic blood pressure, as well as total and LDL cholesterol, in a series of randomized trials (Table 3) [103, 106, 113]. Furthermore, the DASH diet allows for modifications which may enhance long-term adherence while maintaining the relevant cardiometabolic benefits. For example, the OmniHeart trial compared a traditional DASH diet with two modified diets which partially substituted carbohydrates with either healthy protein or fats, and all three diets resulted in reductions in systolic and diastolic blood pressure and LDL cholesterol [107]. Beyond blood pressure and lipid control, several interventional and observational studies have demonstrated the benefits of the DASH diet in reducing the risk of cardiovascular disease (CVD) [93, 114, 115], type 2 diabetes [97, 116], and mortality [94, 117–119]. For instance, among female nurses, those who were most adherent to the DASH diet had 24% lower risk of incident CHD and 29% lower risk of CHD mortality compared to those who were least adherent to the DASH diet [115].

Table 3.

Randomized trials and secondary analyses reporting on the effects of the DASH diet on gout/hyperuricemia and cardiometabolic endpoints

Study (N*)	Gout/hyperuricemia effects	Cardiometabolic effects	Comments
DASH (n = 459 participants not on antihypertensives at baseline)	0.25 mg/dL ↓ in serum urate with DASH diet as compared to control diet (p=0.004) [102•] 0.17 mg/dL ↓ in serum urate with FV diet versus control diet (p=0.051) [102•] Effects ↑ with increasing baseline SU levels with DASH diet, but not FV diet [102•] SU changes strongly associated with changes in LDL but not SBP or DBP [102•]	5.5 mmHg ↓ in SBP and 3.0 mmHg ↓ in DBP with DASH diet as compared with control diet [103]. 13.7 mg/dL ↓ in total cholesterol and 10.7 mg/dL ↓ in LDL with DASH diet as compared with control diet [104].	Serum urate data derived from n=327 participants with serum urate data available
DASH-Sodium (n = 412 participants not on antihypertensives at baseline)	0.35 mg/dL ↓ in serum urate with DASH diet as compared to control diet [105]. Among those with baseline SU 6 to <7 mg/dL, 0.76 mg/dL ↓ in serum urate with DASH diet as compared to control diet [105]. Among those with baseline SU ≥7 mg/dL, 1.29 ↓ in serum urate with DASH diet as compared to control diet [105].	2.2 to 5.9 mmHg ↓ in SBP and 1.0 to 2.9 mmHg ↓ in DBP with DASH diet as compared with control diet [106].	Serum urate data derived from n=103 participants with serum urate data available [105].
OmniHeart Trial [107] (n = 164 participants with pre- or stage 1 hypertension)	0.16 mg/dL ↓ in serum urate with protein diet at 6 weeks, but no change in serum urate with carb or unsat fat diets [108] Among those with baseline SU ≥ 6 mg/dL, 0.38 ↓ in serum urate and no difference across diets [108] SU changes strongly associated with changes in LDL and serum creatinine but not SBP or DBP [108]	8.2 to 9.5 ↓ in SBP and 4.1 to 5.2 ↓ in DBP at 6 weeks compared to baseline. Compared to carb diet, protein and unsat fat diets resulted in greater reduction in SBP and DBP 11.6 to 14.2 mg/dL ↓ in LDL at 6 weeks compared to baseline for all diets. Compared to carb diet, protein diet resulted in greater reduction in LDL Compared to carb diet, protein and unsat fat diets resulted in greater improvements in HDL and reduction in triglycerides	3 variations of DASH diet, no “control” diet: (1) Carb diet = most similar to DASH diet; (2) protein diet = partial replacement of carbohydrates with protein; (3) unsat fat diet = with partial replacement of carbohydrates with unsaturated fat
OmniCarb (n=163 overweight or obese adults without cardiovascular disease) [109]	0.24 and 0.17mg/dL ↓ in serum urate when reducing GI while maintaining a low carb diet or high-carb diet, respectively. Biggest ↓ in serum urate (by 0.27 mg/dL) when simultaneously reducing GI and ↑ % carb, potentially due to high % of animal protein in low-carb diet	N/A	Randomized crossover study of 4 diets with SU levels measured after each 5-week diet period: (1) high GI-high % carb; (2) low GI-low % carb; (3) low GI-high % carb; (4) high GI-low % carb.
PREMIER (n = 810 adults with above optimal BP not on antihypertensives)	N/A	4.3 mmHg ↓ in SBP and 2.6 mmHg ↓ in DBP with DASH + established interventions** as compared with control group [110]. 12% ↓ 10-year CHD risk (Framingham) with DASH + established interventions** as compared with control group [111].	Control group received advice and educational materials on nonpharmacologic factors that affect BP during single study visit.
DiGO (n=43 gout patients, not using urate lowering therapies) [112•]	0.55 mg/dL ↓ in serum urate for DASH group during period 1, and no change for control group	N/A	Randomized trial comparing the effects of provision of DASH-patterned foods with self-directed shopping and general dietary guidance

CVD cardiovascular disease

^*N represents that of original trial

^**Behavioral intervention that implemented established recommendations regarding weight loss if overweight/obese, physical activity, and dietary sodium and alcohol intake

Because a significant proportion of patients with gout and hyperuricemia suffer from hypertension (74% and 50%, respectively) [120], the DASH diet is indicated in the majority of patients with gout as long as there are no harms with regard to gout and hyperuricemia endpoints. Recent studies have consistently found urate-lowering benefits of the DASH diet in secondary analyses of randomized trials (Table 3) and inverse associations with gout risk in prospective cohort studies. For instance, a secondary analysis of the DASH-Sodium trial showed that the DASH diet resulted in a reduction in serum urate of 0.35 mg/dL compared to controls; in a subgroup analysis, the reduction in serum urate was more pronounced among those with baseline hyperuricemia, with a reduction of 0.76 mg/dL and 1.29 mg/dL among those with serum urate 6–7 mg/dL and ≥7 mg/dL, respectively [105]. The same finding was observed in a recently published ancillary analysis of the original DASH trial, which also demonstrated a more potent urate-lowering effect of the DASH diet as a whole compared to a third arm that consumed large amounts of high-fiber fruits and vegetables [102•]. Interestingly, the SU reductions in both the DASH and DASH-Sodium trials were associated with reductions in levels of LDL cholesterol rather than blood pressure, something that was also observed in a post hoc analysis of the OmniHeart trial [108]. Furthermore, recent randomized, controlled, crossover pilot trial studied the effects of a 4-week dietician-directed grocery delivery, modeled after the DASH diet, on serum urate, compared to self-directed grocery shopping, and found a mean serum urate reduction of 0.55 mg/dL for the intervention group during the pre-crossover period, compared to 0.00 mg/dL for the control group [112•]. Finally, while the clinical endpoint of gout is difficult to study in a controlled trial, high adherence to the DASH diet has been associated with 32% lower risk of incident gout in prospective cohort studies of male [121] and female [101] health professionals in the USA.

Weight Loss Interventions for Gout and Beyond

As previously mentioned, adiposity has been identified time and time again as a major modifiable risk factor for gout and cardiometabolic comorbidities. Thus, multiple studies have demonstrated the benefits of weight loss, whether through changes in diet, bariatric surgery, physical activity, or a combination thereof, on relevant gout and cardiometabolic endpoints (Table 4). With respect to dietary weight loss trials, a secondary analysis of the Dietary Intervention Randomized Controlled Trial (DIRECT) [99] found that all three weight loss diets (low-fat/calorie-restricted, Mediterranean/calorie-restricted, and low-carbohydrate/calorie-non-restricted) resulted in a mean reduction in serum urate from baseline of 0.8 mg/dL over 6 months. The effects were more pronounced among those with baseline hyperuricemia ≥ 7 mg/dL, with a serum urate reduction from baseline ranging from 1.9 mg/dL with the low-fat diet to 2.4 mg/dL with the low-carbohydrate diet [100••]. Additionally, a small pilot study of 13 gout patients assigned to a weight loss diet that consisted of calorie restriction with high intake of protein and lower consumption of carbohydrates and saturated fats found that mean serum urate levels decreased from 9.6 to 7.9 mg/dL and the frequency of monthly gout flares decreased from 2.1 to 0.6 [54]. Lastly, a recent randomized controlled trial investigated weight loss through hypocaloric diet and weekly dietician visits as a treatment for gout in patients with comorbid obesity and found that weight loss in the intensive dietary intervention arm during the 16-week trial was more significant. However, although absolute differences in serum urate, fatigue, and pain were apparent in a way that favored the dietary intervention group, statistical significance could not be achieved in this small study limited to 61 participants [130]. Nevertheless, together these studies call into question the current practice of recommending a low-purine (i.e., low-protein, thus high-carbohydrate or fat) diet for patients with gout.

Table 4.

Cardiometabolic and urate effects of weight loss by diet and other measures

	Gout/Hyperuricemia Effects	Cardiometabolic Effects	Comments
DIRECT [99] (n = 322 overweight/obese subjects)	0.8 mg/dL ↓ in serum urate at 6 months with all dietary interventions compared to baseline [100••]. Among those with baseline hyperuricemia (SU ≥ 7 mg/dL), 1.9 to 2.4 mg/dL ↓ in serum urate at 6 months with all dietary interventions compared to baseline [100••].	2.9 to 4.7 kg ↓ in weight with all dietary interventions compared to baseline. 6.3 to 8.4 mg/dL ↑ in HDL and 0.6 to 1.1 ↓ in total cholesterol to HDL ratio with all dietary interventions compared to baseline.	3 dietary interventions: (1) low-fat, restricted calorie; (2) Mediterranean, restricted calorie; (3) low-carbohydrate, non-restricted calorie (modeled after Atkins diet) [99]. Serum urate data derived from n = 232 participants with serum urata data available [100••].
Dessein et al. [54] (n = 13 gout patients)	1.7 mg/dL ↓ in serum urate from baseline. 1.5 ↓ flares/month from baseline.	7.7 kg ↓ in weight from baseline. 30.9 mg/dL ↓ in LDL and 248 mg/dL ↓ in triglycerides from baseline.	Dietary intervention includedmoderate calorie and carbohydrate restriction with proportional increase in protein intake.
MRFIT (n = 12,379 men with high cardiovascular risk profile)	3.9-fold ↑ odds of achieving serum urate ≤ 6 mg/dL with ≥10 kg weight loss as compared with no weight change [122]. 0.62 mg/dL ↑ in serum urate with ≥10 kg weight loss as compared with no weight change [122]. 1.6-fold ↑ odds of recurrent gout flares among those with >5% increase in BMI compared to those with no change [123]. 39% ↓ odds of recurrent gout flares among those with >5% decrease in BMI compared to those with no change [123].	18% ↓ risk of incident T2DM among non-smokers in the special intervention arm that included nutritional counseling to produce weight loss [124].	Recurrent gout data derived from n =11,896 men without gout at baseline [123].
Dalbeth et al. [125] (n = 60 participants with T2DM and morbid obesity, including 12 participants with gout)	50% ↑ in number of participants achieving serum urate < 6 mg/dL after bariatric surgery among participants with gout. 31% ↓ in number of participants with serum urate > 7 mg/dL after bariatric surgery among participants without gout.	39.9 kg ↓ in weight after bariatric surgery among participants without gout. 34.0 kg ↓ in weight after bariatric surgery among participants with gout.
Romero-Talamás et al. [126] (n = 99 morbidly obese patients with gout who underwent bariatric surgery)	3.5 mg/dL ↓ in serum urate 13-months post-bariatric surgery compared to baseline. 15.8% ↓ in patients with gout flares months 1–13 post-bariatric surgery compared to 12 months pre-surgery.
Swedish Obese Subjects Study [127] (n = 4047 obese subjects enrolled for at least 2 years)	Greater ↓ in serum urate (8.8%) at 10 years with bariatric surgery as compared with controls [127]. 40% ↓ risk of incident gout with surgery as compared with controls [128] 53% ↓ risk of incident hyperuricemia* with surgery as compared with controls [128].	Greater ↓ in weight (16.3%), glucose (18.4%), insulin (30.3%), and triglycerides (14.8%) at 10 years with surgery as compared with controls [127].	Incident gout and hyperuricemia data derived from n = 3981 obese subjects without gout at baseline [128].
Lu et al. [129] (n=147 obese subjects who underwent bariatric surgery and had serum urate values available)	Greater 12 month ↓ in body weight and serum urate among those with gout (38.2 kg; 2.75 mg/dlL) or hyperuricemia (31.9 kg; 1.68 mg/dL) than nomocemic

^*Hyperuricemia defined as SU > 6.8 mg/dL

Relevance of Physical Activity in Gout and Cardiometabolic Health

While its cardiometabolic benefits are broadly applicable, physical activity is also relevant to gout prevention and care. Like diet, it may have both direct and indirect effects (e.g., impacting adiposity) on gout risk and comorbidities. A prospective study of males found running distance and fitness performance were both associated with a lower risk of incident gout; however, when BMI was adjusted in the model, the association disappeared, indicating the exercise effect was entirely mediated through BMI [131]. Conversely, in two population-based cross-sectional studies [132, 133], levels of physical activity and sedentary behavior were significantly associated with hyperuricemia status, even with adjustment for BMI; a third [134] concluded that high levels of physical activity could attenuate, or even override, the excess mortality risk conferred by hyperuricemia. Regarding gout-specific endpoints, recent data from a mouse model of acute gout suggested that low- or moderate-intensity exercise could mitigate the inflammatory response to monosodium urate (MSU) crystal deposition, while high-intensity exercise was not beneficial [135]. This study also presented cross-sectional data from adults with gout, among whom the physically active participants had a lower frequency of flares than those physically inactive, and lower levels of pain and inflammatory markers. However, as reverse causality is a strong possibility (e.g., severe tophaceous gout restricting physical activity), prospective data are needed to provide clarity about the impact of physical activity and sedentary time on these key outcomes.

Short-Term Dietary Triggers for Gout Flare

Because gout and its associated cardiometabolic comorbidities result from chronic adoption of Western dietary trends, as opposed to short-term dietary indiscretions, its antidote is the implementation of healthier eating patterns in the long-term. In this regard, the dietary recommendations for gout morbidity as well as cardiometabolic comorbidity align very nicely, due to the shared pathogenesis mediated by insulin resistance. However, there are a few foodstuffs for which the long-term recommendations for gout morbidity and cardiometabolic comorbidity management may seem contradictory to short-term recommendations for gout flare prevention. For example, although strict purine avoidance is not advisable in the long-term, short-term exposures to purine-rich foods have been associated with recurrent gout flares in a self-controlled, case-crossover study [136]. Many of the purine-rich foods assessed in this study included fatty animal meats, which should be used only sparingly anyway. Interestingly, this case-crossover study found that consumption of high-purine foods of plant origin, such as peas, lentils, spinach, and asparagus, was not significantly associated with increased risk of recurrent gout flares [136], which again would be consistent with the recommendations of the healthy eating pyramid (Fig. 2).

One purine-rich food item for which the short-term recommendations from a gout flare perspective and long-term recommendations from a gout morbidity and cardiometabolic comorbidity perspective may differ is seafood. In particular, fish rich in omega-3 fatty acids are a notable feature of various healthy dietary patterns, especially the Mediterranean diet, but may be associated with increased risk of gout flares in predisposed individuals. Consequently, it may be advisable to limit the consumption of seafood temporarily if a patient is experiencing frequent gout flares or during the initial phase of urate-lowering therapy (ULT). However, eventually allowing seafood back into the diet once other gout flare prophylaxis measures have been implemented and/or medications have sufficiently lowered serum urate levels is likely overall beneficial. A similar framework may be used to approach the role of moderate wine consumption in one’s diet; wine consumption has been associated with short-term increased risk of gout flares [137] but not identified as a risk for incident gout [138] or hyperuricemia [139] and may have cardiometabolic benefits [140].

Key Knowledge Gaps in Lifestyle Approaches for Gout

Although the scientific and biological rationale behind these dietary recommendations, both for cardiometabolic as well as gout morbidities, are strong and existing data are supportive, there is limited data arising from randomized interventional trials specifically among patients with gout. Clinical trials of the Mediterranean and DASH diets among patients with gout, along with calorie-restriction if applicable, akin to the DIRECT trial [99], would provide even stronger evidence in support of implementing these dietary recommendations in clinical practice. Furthermore, research that incorporates patient preferences and barriers to implementation and adherence would be even more relevant, given the well-known challenges to long-term sustenance of dietary recommendations for the management of chronic conditions. A recent randomized, controlled, crossover trial was conducted to study the effects of a DASH-pattern diet on serum urate levels in a real-world setting among gout patients (n=43) [112•]. The intervention in this study, which was dietician-directed grocery delivery modeled after the DASH diet, was intentionally designed to be looser and more pragmatic than the controlled feeding interventions implemented in prior DASH trials. The findings were promising for the urate-lowering benefits of the DASH-style diet among gout patients, especially when considering the intentionally looser study design, with a mean serum urate reduction of 0.55 mg/dL for the intervention group in the pre-crossover period, compared to 0.00 mg/dL for the control group (self-directed grocery shopping and general dietary advice). However, carryover effects were present in the post-crossover phase without a washout period, and thus, a parallel design with controlled feeding would be needed to evaluate a full benefit of the DASH diet among gout patients, as in the original DASH trials [103, 106].

Significant gaps also exist regarding the impact of physical activity and sedentary behavior on the development of gout. Longitudinal studies are needed to inform this question, and provide guidance on the types, amounts, and levels of activity likely to either accelerate or attenuate the progression of gout.

Practical Role of Dietary Approaches in Gout Care and Public Health

As hitherto outlined, Western lifestyle trends have heavily contributed to the modern gout epidemic, leading to substantial morbidity, comorbidity, and premature mortality among gout patients. As such, implementing dietary changes to counteract these trends should form an important part of holistic gout prevention and care, similar to care of other cardiometabolic conditions such as type 2 diabetes and CHD. Nevertheless, there are several important tenets to keep in mind when implementing risk factor management in gout. Firstly, it is important to recognize that, similar to the accumulation of excess body weight, it takes years, or even decades, of hyperuricemia surpassing the saturation point of urate to build up and sustain the excess urate pool that leads to formation of MSU crystals in gout patients [19]. Thus, depending on their urate-lowering effectiveness, some interventions require more time to sufficiently remove the excess urate pool and make a lasting impact. For example, isocaloric dietary composition change alone is expected to take longer than major weight reduction (e.g., with bariatric surgery and weight loss diet) or quick fixes such as replacing diuretics with urate-lowering antihypertensives such as losartan or calcium channel blockers. Combinations of these factors would make a larger impact. In practice, for patients with asymptomatic hyperuricemia or gout with infrequent flares who do not qualify for pharmacologic ULT, risk factor management, including dietary modifications, is the only indicated intervention. While this is more relevant to patients whose gout is early and mild (usually managed by a primary care physician), this actually represents a large proportion of gout patients. For those who require rheumatology care, dietary modifications should play an adjunctive role that complements, not supplants, the need for effective pharmacologic ULT [5], which is important to emphasize during gout care implementation. In the end, these lifestyle changes can offer substantial protection against the risk of comorbidities and premature mortality and may also help reduce the frequency of gout flares. Unlike ULT or other pharmacotherapy, there are (under most circumstances) few drawbacks to their implementation.

From a public health perspective, our modern, convenience-oriented environments and growing socioeconomic barriers (e.g., food deserts) continue to facilitate the overconsumption of fast and processed foods. This makes it challenging to make lasting healthy dietary changes when surrounded by so much temptation [141] or when more nutritious and healthy options are out-of-reach. Yet the challenge should not be a justification to dismiss the true causes behind it. Effective public health measures to combat the obesity and gout epidemics are likely possible with creative endeavors [142], similar to successful campaigns such as smoking cessation and prevention of driving under the influence, which were initially thought to be difficult due to societal hurdles. For example, a health economic analysis that modeled the impact of a sugar tax on incident gout in the USA suggested this tax could reduce incident gout by nearly 85,000 cases over 15 years and result in a savings of over 25,000 quality-adjusted life years and three billion dollars [143]. As achieving relatively small reductions in serum urate at the population-level (<0.5 mg/dL, on average) is expected to have a huge societal impact on gout burden, it is important to make these public health messages clear and unified to be effective. Importantly, despite the great efficacy of ULT, it is nearly impossible to imagine this drug being used in primary prevention of gout, given the fact that only a portion of gout patients are indicated for ULT when flares are frequent and severe enough.

Conclusion

Dietary recommendations for patients with gout and hyperuricemia should comprehensively address gout morbidity and its cardiometabolic comorbidities. This can be achieved synergistically by following one of several well-established healthy eating patterns, including the Mediterranean and DASH diets, with or without calorie restriction to achieve healthy weight. These approaches can help lower serum urate levels, though they may not obviate the need for ULT when indicated, and would lead to improvements in cardiometabolic risk factors such as insulin resistance, blood pressure, and lipid profiles. This appears particularly notable, as the cardiometabolic benefits are yet unproven, if not controversial, with the available urate-lowering medications to date [144–147]. The conventional low-purine (i.e., low-protein) approach to gout dietary guidance is neither helpful nor sustainable and may lead to detrimental effects related to worsening insulin resistance as a result of substitution of healthy proteins with unhealthy carbohydrates or fats. Rather, by focusing our dietary recommendations on healthy eating patterns which have been proven to reduce cardiometabolic risk factors, as opposed to singular “good” or “bad” food items or groups, the beneficial effects of such diets on relevant gout endpoints should naturally follow for the majority of typical gout cases, mediated through changes in insulin resistance.